Bibliographic details of the publications referred to by author in this specification are collected at the end of the description.
Herbal formulations comprising extracts of more than one herbal plant have been used for centuries in Traditional Chinese Medicine (TCM). There is now an increasing acceptance of their value and therapeutic efficacy in Western medicine. TCM has its own unique and philosophical theory in etiology, pathology, diagnosis, pharmacology and therapeutics. Many concepts surrounding TCM have particular relevance to Western medicine such as viewing parts of the body as an organic whole, considering inter-relations and influences between organs and being aware of relevant adaptation of the human body to the natural environment.
Despite the effectiveness of many herbal formulations in the treatment of a range of conditions, little is known about how the formulations work. Information on the mechanisms of action for herbal formulations would permit the rational design of particular compositions or chemical synthetic production of one or more components of the compositions as well as ensuring that the appropriate composition is selected for a particular ailment or condition.
Androgens are one of a group of steroid hormones which include testosterone and dihydrotestosterone (DHT). The androgens stimulate the development of male sex organs and male secondary sexual characteristics such as beard growth, deepening of the voice and muscle development. The principal source of these hormones is the testis but they are also secreted in small amounts from the adrenal cortex.
Androgens act through an X-linked androgen receptor (AR) to regulate androgen-responsive genes. This in turn leads to a cascade of metabolic events which manifest as androgenic effects including male sexual development in the fetus, secondary sexual development and sperm production at puberty, anabolic processes including muscle growth and bone density, male sex drive (i.e. libido), hair growth, skin condition, and physical stamina in adults (Wilson, 1992).
Naturally occurring and synthetic androgens are used in replacement therapy such as to treat delayed puberty in boys, hypogonadal men, impotence and as anabolic agents and in the treatment of cancer. However, only limited number of natural and synthetic androgens are known. As stated above, testosterone and DHT are examples of natural androgens. Miborelone and mesterolone are examples of synthetic androgens. The chemical structure common to steroidal hormones, including androgens, is the 1,3 -cyclopentanophrenanthrene ring system.
Androgens in the cell bind to the ligand-binding domain (LBD) of the androgen receptor. Upon ligand binding, the androgen receptor which comprises the transactivation domain (TAD), DNA-binding domain (DBD) and the ligand bound LBD adopts a transactivational conformation and translocates to the nucleus where it binds specifically to the androgen-responsive element (ARE) of the androgen-regulated gene. Following the recruitment of DNA polymerase and co-activators to form the quaternary transcription complex, the gene downstream of the ARE is expressed. Hence, the prerequisite of androgen receptor activity is the specific binding of a ligand into the hydrophobic core of the androgen receptor LBD.
As stated above, there are many conditions associated with low androgen levels, hypofunction of the androgen receptor (Yong, 1994; Tut, 1997; Lim, 1997; Yong, 1998; Wang, 1998, Ghadessy, 1999; Ong, 1999; Dowsing, 1999), declining androgen action associated with aging and other conditions.
There is a need to identify naturally occurring compounds and materials generally from non-mammalian sources, which interact with or activate the androgen receptor and/or the androgen-androgen receptor complex leading to transcription of an androgen-responsive gene. There is also a need to identify estrogenic modulating agents, as well as agents modulating the effects of other members of the steroid/nuclear receptor superfamily of proteins. The identification of such compounds and molecules is needed for the development of therapeutic compositions and/or nutraceutic applications.
In work leading up to the present invention, the inventors sought an edible plant extract with steroidogenic properties.
Eucommia Ulmoides OLIVER (Du-Zhong) is a large deciduous tree which originated in China. The bark of the tree (commonly referred to as Cortex eucommiae) has been used for natural medicine since ancient times (Wei, 1955; Li, 1987).
Decoctions of E. Ulmoides (EU) bark have been used for, amongst other things, the relief of back pain, to increase strength, to make bones and muscle strong, to increase recovery from fatigue, to increase ability to remember and to induce an anti-aging effect. Mechanical training and the use of EU leaf extracts co-operatively can increase the ability of rats to avoid lactate accumulation in skeletal muscle and the administration of the EU leaf extract along with light intensity training enhances the ability of a muscle to resist fatigue (Li, 1996b). EU leaves contain compounds similar to the bark and are reported to have similar pharmacological effects. Since irridoid monoglycosides, such as geniposidic acid and aucubin in EU can stimulate collagen synthesis in aged model rats (Li, 1991a), it is thought that the active compound is actually geniposidic acid or aucubin.
Crude extracts of Tochu tea, an aqueous extract of EU leaves, have a suppressing effect on the induction of chromosome aberrations in CHO cells and mice. Out of 17 Tochu tea components, five irridoids (geniposidic acid, geniposide, asperulosidic acid, deacetyl asperulosidic acid and asperuloside) and three phenols (pyrogallo, protocatechuic acid and p-trans-coumaric acid) were found to have anti-clastogenic activity (protective effect against chromosomal aberrations). Since the anti-clastogenic irridoids had an alpha-unsaturated carbonyl group, this structure was considered to play an important role in the anti-clastogenicity (Nakamura, 1997).
Ingestion of EU bark and leaves, and/or their extracts, cause no known side effects.
In accordance with the present invention, the inventors have determined that certain extracts of EU exhibit steroidogenic activity. The identification of the activity in EU extracts permits the rational design of therapeutic protocols and compositions useful in ameliorating the symptoms of disease conditions. It also permits the production of the active agents in the extracts in purified or chemical synthetic form.